FIGURE 8.

Schematic model. Expression of the p14^ARF tumor suppressor triggers both p53-dependent (left panel) and p53-independent (right panel) apoptosis signaling cascades. In p53-proficient cells, p14^ARF induces the physical stabilization of p53 and the consecutive up-regulation of the BH3-only protein Puma (22). Bax and Bak then trigger the permeabilization of the outer mitochondrial membrane, the release of cytochrome c, and the activation of caspases such as caspase-9 and caspase-3/7. In p53-deficient cells, p14^ARF triggers mitochondrial apoptosis via down-regulation of the anti-apoptotic Bcl-2 homologs Mcl-1 and Bcl-x_L. This attenuates their inhibitory effect on pro-apoptotic Bak, which then undergoes an N-terminal conformational change to allow for the activation of mitochondria in the absence of BH3-only protein induction.